The invention relates to a process of preparing 1,5-diaryl-3-substituted pyrazoles of the formula 
wherein
R1, R2, R3 and R4 are the same or different and are individually selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, amino, acetamido, phenyl, halo, hydroxy, lower alkylsulfonyl, lower alkylthio, nitro, trifluoromethyl, omega-trifluoromethyl lower alkoxy, or where R1, R2 or R3, R4 taken together with the phenyl group to which they are attached, form a naphthyl or substituted naphthyl group.
In a preferred embodiment, the invention relates to a process of making 5-(4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-propanamide, a compound of formula Ia, known as tepoxalin. 
The compounds of formula I and method of making and using the compounds of formula I are described in U.S. Pat. No. 4,826,868, issued May 2, 1989, incorporated by reference herein.
Tepoxalin is a potent inhibitor of both the cyclooxygenase and lipoxygenase pathways of the arachidonic acid cascade (U.S. Pat. No. 4,826,868 and Robinson, C., Drugs of the Future, 15, 9. 902 (1990)).
Known methods of synthesizing tepoxalin include the following. U.S. Pat. No. 4,826,868 describes reacting the alcohol, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanol with Jones reagent to form the acid, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanoic acid, which is reacted with dimethylformamide and oxalyl chloride in tetrahydrofuran (xe2x80x9cTHFxe2x80x9d) which is then reacted with methylhydroxylamine hydrochloride and triethylamine in THF.
U.S. Pat. No. 4,898,952 describes a process for making tepoxalin which comprises reacting a hydrazine with a diketoacid to form a pyrazole acid which is reacted with dimethylformamide and oxalyl chloride to yield the pyrazole acid chloride which is reacted with methyl hydroxylamine hydrochloride and triethylamine to yield tepoxalin. The diketoacid is prepared by adding an appropriately substituted acetophenone to a solution of lithium diisopropylamide (LDA made from diisopropylamine and n-butyllithium in THF at low temperature). Alternatively, lithium hexamethyl disilazide may be employed as the base in place of lithium diisopropylamide. Succinic anhydride is then added to this solution to produce the diketoacid.
U.S. Pat. No. 5,117,054 describes a process wherein p-chloroacetophenone is reacted with succinic anhydride to form 4-chloro-xcex3,xcex5-dioxo-benzenehexanoic acid which is reacted with acetic anhydride or acetyl chloride to yield 5-[2-(4-chlorophenyl)-2-oxoethylidene]dihydro-2(3H)-furanone. This compound is then added to a mixture of N-methylhydroxylamine hydrochloride and an amine base such as triethylamine, Hunig""s base, pyridine or lutidine and a solvent such as methylene chloride or chloroform to form 4-chloro-N-hydroxy-N-methyl-xcex3,xcex5-dioxo-benzenehexanamide which is combined with 4-methoxyphenyl hydrazine hydrochloride, an amine base as described above in an alcoholic solvent such as methanol, ethanol or propanol.
The preparation of 4-chloro-xcex3,xcex5-dioxo-benzenehexanoic acid from p-chloroacetophenone utilizing various bases selected from lithium diisopropylamide (LDA); LDA.LiCl; magnesium diisopropylamide (MDA); MDA.lLiBr; MDA.2LiBR or lithium bis (trimethylsilyl) amide was disclosed in Murray et al, Synthesis 1991, p. 18-20.
Due to cost, toxicity, and hazard considerations, it is desirable to be able to synthesize 1,5-diaryl-3-substituted pyrazoles, particularly tepoxalin, without the reagents lithium hexamethyl disilazide, oxalyl chloride and methylene chloride and without excess p-chloroacetophenone.
The current invention produces tepoxalin in a much higher over-all yield and at a decreased cost than the known processes.
The invention relates to a process for preparing a compound of the formula I 
wherein
R1, R2, R3 and R4 are the same or different and are individually selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, amino, acetamido, phenyl, halo, hydroxy, lower alkylsulfonyl, lower alkylthio, nitro, trifluoromethyl, omega-trifluoromethyl lower alkoxy, or where R1, R2 or R3, R4 taken together with the phenyl group to which they are attached, form a naphthyl or substituted naphthyl group;
comprising reacting a compound of formula II 
wherein R3 and R4 are as described above, with succinic anhydride and an alkoxide base to form the corresponding compound of formula III 
wherein R3 and R4 are as described above, which is reacted with a compound of formula IV 
wherein R1 and R2 are as described above, to form a corresponding compound of formula V 
wherein R1, R2, R3 and R4 are as described above, reacting the compound of formula V with an alcohol to form the corresponding ester of formula VI 
wherein R1, R2, R3 and R4 are as described above and R is lower alkyl or cycloalkyl, and reacting the ester of formula VI with N-methylhydroxylamine hydrochloride and a base to form the corresponding compound of formula I.
In the above formula, R1, R2, R3 and R4 are substituents on phenyl rings, where phenyl rings substitute for hydrogen atoms at positions 1 and 5 of the pyrazole ring. It is preferred that at least one of R1 and R2, and one of R3 and R4 be substituted at the 4-positions of their respective phenyl rings.
Lower aklyl radicals include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl, neopentyl, n-hexyl, 1-methylpentyl, 3-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 2-hexyl, 3-hexyl, octyl and the like.
Lower alkoxy shall mean oxygen ethers formed from a before-described lower alkyl group. Exemplary radicals include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, and the like.
Lower alkylthio radicals of R1, R2, R3 and R4 are thio ethers and are thus analogous to the ethers described above.
Halo radicals preferably include chloro and bromo, as well as fluoro and iodo.
Lower alkylsulfonyl radicals contain a before-described lower alkyl radical bonded to an SO2 moiety that is itself also bonded to a phenyl ring. Exemplary lower alkylsulfonyl radicals thus include methylsulfonyl, ethylsulfonyl, 2-ethylbutylsulfonyl and the like.
An omega-trifluoromethyl lower alkoxy radical is a lower alkoxy radical as before described that additionally includes a trifluoromethyl group at a position farthest on the alkyl chain from the place of bonding to the phenyl ring. Exemplary of such radicals are the 2,2,2-trifluoroethoxy.
Naphthyl and substituted naphthyl radicals can replace an aryl group herein at either the 1- or 2-positions to provide 1-naphthyl or 2-naphththyl substituents respectfully. Substituents on the naphthyl radicals can be any of those described herein as being useful aryl substituents. Exemplary substituted 1- and 2-naphthyls include 6-methoxy-2-naphthyl and the like.
As used herein, unless otherwise noted, the term xe2x80x9clowerxe2x80x9d when used with alkyl or alkoxy means a carbon chain composition of 1-6 carbon atoms.
The term xe2x80x9calkoxide basexe2x80x9d refers to a lower primary alkoxide, secondary alkoxide, or tertiary alkoxide such as, methoxide, ethoxide, 2-propoxide, tert-butoxide and the like. The preferred base is a tertiary alkoxide and preferably potassium tert-butoxide.
The invention relates to a process of preparing a compound of the formula I 
comprising reacting a compound of formula II 
with succinic anhydride and an alkoxide base to form a corresponding compound of formula III 
which is reacted with a compound of formula IV 
to form a corresponding compound of formula V 
reacting the compound of formula V with an alcohol to form the corresponding ester of formula VI 
wherein R is lower alkyl, such as methyl, ethyl, isopropyl, preferably ethyl, or aryl, and reacting the ester of formula VI with N-methylhydroxylamine hydrochloride and an appropriate base, such as an alkoxide base, amine base or inorganic base such as NaOH or KOH, preferred is sodium ethoxide in ethanol, to form the corresponding compound of formula I.
In a preferred embodiment, the invention relates to a process of making compound of formula I wherein 
In a particularly preferred embodiment, the invention relates to a process of making tepoxalin (Ia), wherein R1 is 4-OMe and R3 is 4-Cl, R2 is H and R4 is H. 
As set forth in Scheme 1, a compound of formula II, a known compound or compound prepared by known methods, is reacted with succinic anhydride and an alkoxide base such as Li, Na, or K tert-alkoxide, preferably K-tert-alkoxide, in a polar aprotic solvent such as dimethylformamide, (DMF) or THF, preferably DMF, preferably at an initial temperature from about xe2x88x925 to 20xc2x0 C., more preferably at 0-5xc2x0 C., particularly preferred at 0xc2x0 C., then heating to a temperature of 45-50xc2x0 C. preferably at 45xc2x0 C. to form the corresponding compound of formula III.
Preferably, 1 equivalent each of a compound of formula II, and succinic anhydride is reacted with 2 equivalents of an alkoxide base.
The compound of formula III is treated with, a compound of formula IV, a known compound or compound prepared by known methods, or preferably its HCl salt and a base such as KHCO3, NaHCO3, KOH, or NaOH, preferably NaHCO3, in a lower alcohol solvent such as methanol, ethanol, or 2-propanol, preferably methanol, preferably at a temperature of from about 45 to 55xc2x0 C., to form the corresponding compound of formula V. The compound of formula V is isolated by known methods preferably filtration to remove NaCl, seeding and cooling of the filtrate, and filtration to isolate the compound of formula V.
The compound of formula V is reacted in an alcohol solvent such as methanol, ethanol, 2-propanol, or benzyl alcohol, preferably ethanol, with a catalytic amount of an acid, such as sulfuric acid, hydrochloric acid, or p-toluene sulfonic acid at reflux temperature to produce the corresponding ester of formula VI (methyl, ethyl, isopropyl, or benzyl with ethyl being preferred).
The ester of formula VI is isolated by conventional means such as concentration, seeding, and filtration of the resulting solid. The ester of formula VI is treated with N-methylhydroxylamine hydrochloride (as a solid or as an alcoholic solution which has been prepared from an aqueous solution)and a base such as sodium methoxide, sodium ethoxide, sodium benzyl oxide or, sodium isopropoxide (preferably sodium ethoxide) or N-methyl hydroxylamine free base (a known compound) in an alcoholic. solvent such as methanol, ethanol, 2-propanol, or benzyl alcohol (preferably ethanol)to form the product of formula I. The product is isolated by known methods, preferably aqueous quench followed by filtration.
Alternatively, the ester of formula VI is not isolated. In this case, the compound of formula V is treated with an alcohol such as methanol, ethanol, isopropanol, or benzyl alcohol, preferably ethanol, and a catalytic amount of an acid such as sulfuric acid, hydrochloric acid, or p-toluene sulfonic acid and heated to reflux to form the ester of formula VI and the reaction cooled. The resulting solution of the ester of formula VI is reacted directly with N-methylhydroxylamine hydrochloride (as a solid or as an alcoholic solution which has been prepared from an aqueous solution) and basified with an appropriate base such as sodium methoxide, sodium ethoxide, sodium benzyl oxide or, sodium isopropoxide, preferably sodium ethoxide, to produce the product of formula I. The product is isolated by known methods, preferably aqueous quench followed by filtration.
Alternatively, neither the acid of formula V or the ester of formula VI is isolated, and the compound of formula III is converted (without isolation of V or VI) to product of formula I. In this case, the compound of formula III is treated with a compound of formula IV, a known compound or compound prepared by known methods, or preferably its HCl salt and a base such as KHCO3, NaHCO3, KOH, or NaOH, preferably NaOH, in a lower alcohol solvent such as MeOH, EtOH, or 2-propanol, preferably ethanol, preferably at a temperature of from about 20 to 55xc2x0 C. (preferably at ambient temperature, approximately 25xc2x0 C.) to form the corresponding compound of formula V. The resulting mixture of the compound of formula V is then treated with an acid, such as sulfuric acid, hydrochloric acid, or p-toluene sulfonic acid and heated to reflux to produce the corresponding ester of formula VI. The resulting reaction mixture of the ester of formula VI is then treated directly with N-methylhydroxylamine hydrochloride (as a solid or as an alcoholic solution which has been prepared from an aqueous solution) and basified with an appropriate base such as sodium methoxide, sodium ethoxide, sodium benzyl oxide or, sodium isopropoxide, preferably sodium ethoxide, to produce the corresponding product of formula I. The product is isolated by known methods, preferably aqueous quench followed by filtration.
In another embodiment, the claimed invention relates to a process of making an intermediate of formula III 
comprising reacting a compound of formula II with succinic anhydride in an alkoxide base.
In addition, the claimed invention relates to a process for preparing 1,5-diaryl-3-substituted pyrazoles of formula I, particularly tepoxalin, comprising reacting a compound of formula V with an alcohol to form the corresponding ester of formula VI (where for example R=Me, Et, iPr, preferably Et) and reacting the corresponding ester of formula VI with N-methylhydroxylamine hydrochloride.
This invention also relates to the novel intermediate of formula VI (where for example R is methyl, ethyl or isopropyl preferably ethyl).